Processes for preparing cycloalkylized



United States Patent M 3,156,686 PROCESSES FR PREPARE JG CYCLQALKYMZED 2,3DEHYDRQ-d, l-BENZTll-HAZHNES Gerhard Haclrmack, Aurnuh'le, near Hamburg, and Walter Krastinat, Hamburg-Niendorf, Germany, assignnrs to Chernisehe Fabrik Promonta G.m.h.ll., Hamburg, Germany, a body corporate of Germany No Drawing. Filed Apr. 27, B61, er. No. 105,872 Claims priority, application Gzrmany, Apr. 28, 1%0,

21,31 3 Claims. (Cl. 260-243) The present invention relates to a process for the production of compounds of the following general formula:

nn lagasifii a in which formula R, which may be at any desired positions of the aromatic ring, represents a hydrogen atom or a monovalent radical, particularly a halogen atom, for example chlorine, bromine, fluorine, or an alkyl or alkoxy group, Z represents an aliphatic bridge member connecting the carbon atoms 2 and 3 to form a ring, the said bridge member having from 3 to 6 carbon atoms, which in their turn can be substituted by other groups, for example alkyl or alkoxy.

These compounds are prepared according to the invention by intramolecular transposition of spiro compounds of the following general formula:

In this formula, R has the meaning indicated above, while A represents an aliphatic chain with 4 to 7 carbon atoms, which can be substituted, for example by alkyl or alkoxy groups. A forms, together with the carbon atom 2 of the thiazoline ring, a ring containing from to 8 carbon atoms.

These spiro compounds are the known 2,2-cycloalkylated benzthiazolines, which are, for example readily obtainable from o-aminothiophenols and ring ketones (see for example H. J. Teuber and H. Waider, Chem. Ber. 91, 234144 (1958)). The melt without decomposition and some can also be distilled or sublimed, also Without decomposition. I

According to the invention, a peculiar and hitherto completely unknown transposition to the cycloalkylated 2,3-dihydro-1,4-benzthiazines takes place with these compounds at relatively high temperature.

I The underlying principle of this invention is illustrated by the following reaction scheme:

Thus, 2,2-pentamethylene benzthiazoline, which can for example be prepared in an almost quantitative yield by reaction of o-aminothiophenol with cyclohexanone, is transposed into 2,3-tetramethylene-2,3-dihydro-1,4-benzthiazine.

The transposition can be carried out in the melt or also in the presence of suitable solvents, if necessary under pressure, by heating to relatively high temperature, more especially between 240 and 320 C. It is expedient in this case to work in an inert gas atmosphere, advanta- 3,156,686 Patented Nov. 10, 1964 geously under nitrogen, in order to avoid decomposition due to oxidation. The process can for example be carried out continuously in a throughflow heater. It is also possible to make use of the known process for the production of benzthiazoline compounds as starting products for the transposition by the benzthiazolines being transformed in situ in accordance with the data of the invention into the corresponding benzthiazoline compounds.

The reaction products can be isolated and purified in known manner.

Among the cycloalkylated dihydrobenzthiazines readily obtainable in this manner, it is only the 2,3-tetramethylene-2,3-dihydro-1,4-benzthiazine, the hexahydrophanthiazine, which is already known in the literature. 0. Hrornatka, I. Augl, M. Vaculny and H. Petrousek (Mh. Chem. 89, 517 (1958)) were able for the first time to isolate hexahydrophenthiazine with the subsequent treatment of a reaction of sodium o-aminothiophenol with Z-chlorocyclohexanone, as described by K. Fujii (Yaku gaku Zasshi 77, 352 (1957); Chem. Abstr. '51 12l01f (1957)). A compound with the melting point 81 C., frequently designated as hexahydrophenthiazine in the literature prior to this Work has been identified by the Work of O. Hromatka, M. Vaculny, H. Petrousek and F. Grass (Mh. Chem. 88, 307 (1957)) and F. Asinger, M. Thiel and H. Kaltwasser (Ann. Chem. 606, 67 (1957)) as Z-hydroxy cyclohexyl-2-aminophenyl sulphide.

The cycloaikylated 2,3-dihydro-1,4-benzthiazines are bases which form salts with strong acids. The salts are however readily split hydrolytically. The picrates which are readily obtainable are especially suitable for characterisation purposes.

The compounds which can be prepared by the new process can more especially be employed as anthelmintical agents.

The invention is further illustrated by the following examples:

Example 1 250 g. of 2,2-pentamethylene benzthiazoline are heated for 6 hours in a stream of nitrogen to 260 C. The transposed product is allowed to cool to about 50 C., and it is taken up while still liquid in cc. of methanol. After a short time, 2,3-tetramethylene-2,3-dihydro-1,4- benzthiazine and also in some cases a little unreacted starting material is crystallised out. The suction-filtered product which is still moist with methanol is taken up, together with 175 g. of alcohol-moist picric acid, in such a quantity of alcohol that everything just dissolves at boiling temperature. 2,3-tetramethylene-2,3-dihydro-1,4- benzthiazine picrate immediately crystallises out from the solution. The melting point of the pure compound is at 168 to 168.5" C.

The free base can be isolated from the picrate by stirring out with excess sodium bicarbonate in aqueous solution. By recrystallisation from methyl alcohol, pure 2,3- tetramethylene-2,3-dihydro-1,4-benzthiazine with the melt ing point 101 C., is obtained. The hydrochloride melts at 202 to 203 C. The purification of the crude product forming after the transposition can also be effected by distillation. 2,3-tetramethylene-2,3-dihydro-1,4-benzthiazine boils at 136 C./B.P.'

Example 2 picrate is at C.

2,3-pentamethylene-2,3-dihydro-1,4- benzthiazine melts at 106 C. The melting point of the Example 3 20 g. of 2,2-pentamethylene-S-chloro-benzthiazoline of melting point 96 C., was heated in the molten state at 260 C., for four hours. The crude product was distilied in vacuum. The fraction distilling over between 160 and 190 C., yields after recrystallisation from alcohol pure 2,3 tetramethylene 2,3 dihydro 6 chloro 1,4 benzthiazine, melting point 168 C.

What We claim is:

1. A process for the production of compounds corresponding to the formula in which R is selected from the group consisting of hydrogen and halogens, and Z stands for hydrocarbon chain which connects the carbon atoms in the 2 and 3 position and is selected from the group consisting of and CH CH CH CH CH comprising heating spiro-compounds corresponding to the formula R I so A References Cited in the file of this patent UNITED STATES PATENTS Muth July 19, 1932 OTHER REFERENCES Hromatka et al.: I, Monatsh. Chem., vol. 88, pp. 307- 16 1957 Teuher et al.: Chem. Ber., Vol. 91, 2341-44 (1958).

Hroniatka et al.: II, Monatsh. Chem, vol. 89, pp. 517- 25 (1958). 

1. A PROCESS FOR THE PRODUCTION OF COMPOUNDS CORRESPONDING TO THE FORMULA 